Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial

Leopoldine A. Wilbrink, Ilse F. de Coo, ICON study group, Patty G.G. Doesborg, Wim M. Mulleners, Onno P.M. Teernstra, Eveline C. Bartels, Katja Burger, Frank Wille, Robert T.M. van Dongen, Erkan Kurt, Geert H. Spincemaille, Joost Haan, Erik W. van Zwet, Frank J.P.M. Huygen, Michel D. Ferrari*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

32 Citations (Scopus)

Abstract

Background: Occipital nerve stimulation (ONS) has shown promising results in small uncontrolled trials in patients with medically intractable chronic cluster headache (MICCH). We aimed to establish whether ONS could serve as an effective treatment for patients with MICCH. Methods: The ONS in MICCH (ICON) study is an investigator-initiated, international, multicentre, randomised, double-blind, phase 3, electrical dose-controlled clinical trial. The study took place at four hospitals in the Netherlands, one hospital in Belgium, one in Germany, and one in Hungary. After 12 weeks’ baseline observation, patients with MICCH, at least four attacks per week, and history of being non-responsive to at least three standard preventive drugs, were randomly allocated (at a 1:1 ratio using a computer-generated permuted block) to 24 weeks of occipital nerve stimulation at either 100% or 30% of the individually determined range between paraesthesia threshold and near-discomfort (double-blind study phase). Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy. In weeks 25–48, participants received individually optimised open-label ONS. The primary outcome was the weekly mean attack frequency in weeks 21–24 compared with baseline across all patients and, if a decrease was shown, to show a group-wise difference. The trial is closed to recruitment (ClinicalTrials.gov NCT01151631). Findings: Patients were enrolled between Oct 12, 2010, and Dec 3, 2017. We enrolled 150 patients and randomly assigned 131 (87%) to treatment; 65 (50%) patients to 100% ONS and 66 (50%) to 30% ONS. One of the 66 patients assigned to 30% ONS was not implanted and was therefore excluded from the intention-to-treat analysis. Because the weekly mean attack frequencies at baseline were skewed (median 15·75; IQR 9·44 to 24·75) we used log transformation to analyse the data and medians to present the results. Median weekly mean attack frequencies in the total population decreased from baseline to 7·38 (2·50 to 18·50; p<0·0001) in weeks 21–24, a median change of –5·21 (–11·18 to –0·19; p<0·0001) attacks per week. In the 100% ONS stimulation group, mean attack frequency decreased from 17·58 (9·83 to 29·33) at baseline to 9·50 (3·00 to 21·25) at 21–24 weeks (median change from baseline –4·08, –11·92 to –0·25), and for the 30% ONS stimulation group, mean attack frequency decreased from 15·00 (9·25 to 22·33) to 6·75 (1·50 to 16·50; –6·50, –10·83 to –0·08). The difference in median weekly mean attack frequency between groups at the end of the masked phase in weeks 21–24 was –2·42 (95% CI –5·17 to 3·33). In the masked study phase, 129 adverse events occurred with 100% ONS and 95 occurred with 30% ONS. None of the adverse events was unexpected but 17 with 100% ONS and eight with 30% ONS were labelled as serious, given they required brief hospital admission for minor hardware-related issues. The most common adverse events were local pain, impaired wound healing, neck stiffness, and hardware damage. Interpretation: In patients with MICCH, both 100% ONS intensity and 30% ONS intensity substantially reduced attack frequency and were safe and well tolerated. Future research should focus on optimising stimulation protocols and disentangling the underlying mechanism of action. Funding: The Netherlands Organisation for Scientific Research, the Dutch Ministry of Health, the NutsOhra Foundation from the Dutch Health Insurance Companies, and Medtronic.

Original languageEnglish
Pages (from-to)515-525
Number of pages11
JournalThe Lancet Neurology
Volume20
Issue number7
DOIs
Publication statusPublished - Jul 2021

Bibliographical note

Funding Information:
MDF reports grants and consultancy or industry support from Electrocore, Medtronic, Eli Lilly, Amgen, Novartis, and TEVA, and independent support from The Netherlands Organisation for Scientific Research, The Netherlands Organisation for Health Research and Development, The Dutch Brain and Heart Foundations, The Dutch Ministry of Health, and The NutsOhra Foundation from the Dutch Insurance Companies. FJPMH reports grants and consultancy fees from Abbott, Saluda, and Pfizer, and independent support from The Netherlands Organisation for Health Research and Development. IFdC reports travel grants from Electrocore. All other authors report no competing interests.

Funding Information:
We gratefully acknowledge logistical support from Dr R Buschman (Medtronic BV, Eindhoven, Netherlands). The study was funded by the Spinoza 2009 Lifetime Scientific Research Achievement Premium from the Netherlands Organisation for Scientific Research, the Dutch Ministry of Health (as part of a national provisional reimbursement programme for promising new treatments), the NutsOhra Foundation from the Dutch Health Insurance Companies, and an unrestricted grant from Medtronic, all to MDF. The corresponding author had full access to all the data in the study and had final responsibility for the decision to sumit for publication.

Publisher Copyright:
© 2021 Elsevier Ltd

Fingerprint

Dive into the research topics of 'Safety and efficacy of occipital nerve stimulation for attack prevention in medically intractable chronic cluster headache (ICON): a randomised, double-blind, multicentre, phase 3, electrical dose-controlled trial'. Together they form a unique fingerprint.

Cite this